National Advisory Council for Human Genome Research
Summary of Meeting

Natcher Conference CenterBethesda, Md.

September 13, 2004

The open session of the National Advisory Council for Human Genome Research
was convened for its thirty-eighth meeting at 8:40 a.m. on September 13, 2004
at the Natcher Conference Center, National Institutes of Health, Bethesda, MD.
Francis Collins, Director of the National Human Genome Research Institute, called
the meeting to order.

The meeting was open to the public from 8:40 a.m. until 12:30 p.m. on September
13, 2004. In accordance with the provisions of Public Law 92-463, the meeting
was closed to the public from 12:30 p.m. on September 13, 2004 until adjournment
for the review, discussion, and evaluation of grant applications.

Introduction of Liaisons and New Employees

Mark Guyer introduced four recently approved council members currently serving
in the capacity of ad hoc council members: Marilyn Coors from the University
of Colorado Health Sciences Center, Geoff Duyk from TPG Ventures, Sean Eddy
from the Howard Hughes Medical Institute, Washington University School of Medicine
and Jeff Murray from the University of Iowa.

Dr. Guyer welcomed members of the press and liaisons from professional societies:
Sharon Olsen of the International Society of Nurses in Genetics, Edward Kloza
of the National Society of Genetic Counselors, Jennifer Couzin of Science and
Andrew Hawkins of The Blue Sheet.

Dr. Collins presented certificates of appreciation and thanked Ron Davis, Kim
Nickerson, Janet Rowley and Rick Lifton, who have all completed their terms
as council members.

Approval of Minutes

The minutes from the May 2004 Council meeting were approved as submitted.

Future Meeting Dates

The following dates were proposed for future meetings: February 7-8, 2005,
May 23-24, 2005, September 12-13, 2005, February 12-14, 2005, May 22-23, 2006
and September 11-12, 2006.

Director's Report

General Announcements

Dr. Collins reflected upon the life of Francis Crick who passed away July 28,
2004, at the age of 88, following a prolonged battle with colon cancer. He was
trained as a physicist but was widely regarded as one of the twentieth century's
most significant figures in biology. John Fletcher, former ELSI grantee and
the first Chief Ethics Officer of the NIH Clinical Center, passed away on May
27, 2004. Dr. Fletcher was professor emeritus of biomedical ethics in internal
medicine at the University of Virginia medical school.

NHGRI Grantee Michael Eisen from Lawrence Berkeley National Laboratory received
the Presidential Early Career Award for Scientists and Engineers (PECASE) on
September 9, 2004, for his pioneering work in developing novel computational
methods and tools to identify patterns in genomic data.

NIH released a notice regarding the NIH Policy on Sharing of Model Organisms
for Biomedical Research on May 7, 2004, reaffirming support for the concept
of timely sharing and distribution of biomedical resources. Beginning October
1, 2004, all investigators submitting an application or contract proposal are
expected to include a specific plan for data sharing, or a justification of
why they cannot abide by this policy.

New NHGRI Initiatives

An RFA for Intellectual Property Rights in Genetics and Genomics was released
June 2, 2004, to encourage the study of the role of laws and policies regarding
intellectual property rights in genetics and genomics research and development.

NHGRI is involved in two recently released NIH roadmap RFAs. An RFA for Molecular
Libraries Screening Instrumentation was released July 13, 2004, to develop innovative
instrumentation to accelerate the pace and maximize the efficiency of molecular
library high throughput screening. An RFA for the Molecular Libraries Screening
Center Network (MLSCN) was released April 18, 2004. The NIH Chemical Genomics
Center, which will be housed within the NHGRI Division of Intramural Research,
is the first of the screening centers in this network. Additional information
about the NIH Roadmap can be found at nihroadmap.nih.gov. More information regarding
the NIH Roadmap effort will also be presented at the February council session.

Recent Scientific Accomplishments and Issues

NHGRI - Extramural Program

On June 25, 2004, NHGRI's extramural division officially relocated from the
main NIH campus in Bethesda, MD to Rockville, MD near the Twinbrook metro station.
In addition, the NIH Intramural Sequencing Center (NISC) and several other NHGRI
intramural laboratories are also expected to relocate to Twinbrook offices on
September 30, 2004.

The sequencing program has been very active since the last council session,
generating sequence from a number of organisms. In addition, a number of press
advisories have been released. On August 4, 2004, NHGRI announced that the Large-Scale
Sequencing Research Network could begin sequencing 18 selected organisms. On
June 8, 2004, NHGRI announced a partnership with the Melbourne-based Australian
Genome Research Facility Ltd. to sequence the Tammar wallaby (Macropus eugenii),
a small member of the kangaroo family. In addition, on July 14, 2004, NHGRI
announced the first draft of the dog (boxer) genome sequence. The team of researchers
from the Broad Institute of MIT and Agencourt Bioscience Corporation assembled
the genome based on seven-fold genome sequence coverage.

A "Workshop on Characterizing Human Genetic Variation" was held on
August 3-4, 2004 to examine potential NHGRI human resequencing efforts and technology
development needs in this area. A number of groups presented data regarding
the status of different technologies. The workshop participants debated the
merits of whole genome shotgun approaches and targeted resequencing of conserved
regions, concluding that a balance of the two should be included in the NHGRI
portfolio. Bob Waterston and David Altshuler co-chaired the meeting.

June 28, 2004, NHGRI announced the award of two new Centers of Excellence in
Genomic Science (CEGS) grants, one at Harvard Medical School in Boston led by
George Church and the other at Johns Hopkins School of Medicine in Baltimore
led by Andrew Feinberg. Council will hear a full review of the CEGS program
at the February 2005 council session.

On August 31, 2004, NHGRI announced the launch of the Centers for Excellence
in ELSI Research (CEER) initiative, led by NHGRI with additional funding from
DOE and NICHD that will establish interdisciplinary research centers to address
ELSI. The first four Centers will be established at Case Western Reserve University,
led by Eric Juengst; Duke University, led by Robert Cook-Deegan; Stanford University,
led by Mildred Cho; and the University of Washington, led by Wylie Burke. In
addition, NHGRI has awarded three exploratory grants to Alexandra Shield at
Georgetown University, Charmaine Royal at Howard University, and Donald Bailey
at the University of North Carolina, Charlotte.

The ENCODE project is an effort to bring together experimental and computational
research methods to identify all functional sequence elements in 1% of the human
genome sequence. A Consortium meeting was held June 28-30, 2004. A second set
of technology development grants will be discussed in closed session. An analysis
working group, to be chaired by Ewan Birney, has been established to help guide
Consortium analyses on specific topics and on an analysis of the overall progress
of the Consortium. A manuscript describing the ENCODE project has been submitted
for publication. The next Consortium meeting is scheduled for November 10 -
11, 2004, immediately preceding the Cold Spring Harbor meeting on the Identification
of Functional Elements in Mammalian Genomes.

Gary Temple has been hired by NHGRI to be the full-time leader of the Mammalian
Gene Collection (MGC) project. Rat full-length cDNAs have recently been added
to the MGC effort. As of August 24, 2004, 32,505 full-ORF sequences have been
submitted to GenBank. These comprise a non-redundant set of 23,834 total clones.
A manuscript in Genome Research describing the current status of the MGC is
in press.

With the goal of profiling ninety mouse tissues in depth by Massively Parallel
Signature Sequencing (MPSS) technology, the Mouse Transcriptome Project was
funded by eleven NIH institutes in October 2003 and is led by NHGRI. The data
from this effort will be immediately deposited in GEO (the NCBI Gene Expression
Omnibus), and will be available in searchable form from GEO as well as the Lynx
Technologies website. A press release will notify the community of the project,
once the data are available.

A Commentary in the September issue of Nature Genetics discusses the consensus
reached at a Banbury meeting on genome-wide mouse mutagenesis (Knockout Mouse
Project) held in October 2003. The consensus, which has been refined since the
meeting, aims to produce and phenotype knockouts for all mouse genes and place
the resources in the public domain.

The ELSI Genetic Variation Consortium (GVC) continues to meet regularly. The
last meeting was held July 12-14, 2004. The meeting provided the opportunity
for Principal Investigators and other key personnel funded for projects to continue
to examine the ethical, legal, and social implications (ELSI) of research on
human genetic variation, learn about other relevant NIH supported research,
and discuss research approaches and findings.

NHGRI - Intramural Program

June 9, 2004, NIH announced the establishment of the NIH Chemical Genomics
Center, based in NHGRI's Division of Intramural Research, under the leadership
of Chris Austin. The Center is expected to be up and running by February 2005.

A consortium of researchers at twelve research institutes, including Joan Bailey-Wilson
at NHGRI, and NCI has discovered a possible inherited component for lung cancer.
The researchers found strong evidence that a lung cancer susceptibility gene
or genes is co-inherited with a genetic marker on human chromosome 6.

NHGRI - Office of the Director

NHGRI held the 2004 annual Current Topics in Genomics Short Course for faculty
and students at minority serving institutions July 26-30, at the NIH campus.
The Course hosted 31 participants from 15 different colleges and universities
across the country and included new components such as interactive sessions,
student lab shadowing, new sessions with OD and DER staff, and curricula development
for the faculty participants in partnership with National Coalition for Health
Professional Education in Genetics (NCHPEG).

The NHGRI website, genome.gov, has been completely redesigned. The new site,
launched June 18, 2004, features improvements in navigation and content organization.

The American Academy of Family Physicians has chosen genomics as the topic for
their 2005 Annual Clinical Focus for their 93,000 members. The official launch
of the ACF 2005 Genomics will be held at the combined 2004 Annual Scientific
Assembly/World Organization of Family Doctors meeting in Orlando, FL, October
13-17, 2004. Dr. Collins will give the keynote address at that event.

NHGRI has been working with the Surgeon General, Richard Carmona, and other
agencies to increase the American public's awareness of the importance of family
history. An effort is underway to develop a user-friendly, web-based tool for
the public to collect family medical history information.

NHGRI - Policy

July 19, 2004, NHGRI launched a new web-based legislative and policy database
that will enable researchers, health professionals and the general public to
more easily locate information on laws and policies related to genetic issues,
such as: genetic testing and counseling, insurance and employment discrimination,
newborn screening, privacy of genetic information and confidentiality, informed
consent, and commercialization and patenting.

The National Academy of Sciences Committee on Intellectual Property Rights
in Genomic and Protein-Related Inventions, co-chaired by Shirley Tilghman and
Rod McKelvie, held its second meeting June 4, 2004, and third meeting August
5, 2004. The committee will issue a report to document the types of patents
that have been issued and to whom, differences in the criteria being applied
by the U.S. and other major patent offices to the examination of such applications,
and to the extent possible, the licensing arrangements for different types of
patented materials. The study will also attempt to evaluate the consequences
of genomic patents on the progress of research.

The House Labor, Health & Human Services, and Education Appropriations
bill was passed in the House on September 9, 2004. The bill provides NIH with
an increase of 2.8% over fiscal year 2004. This is equal to the President's
fiscal year 2005 request. The NHGRI would receive a total of $492 million, which
is $13 million above last year's level. The Senate has not yet taken up the
bill. There were some disturbing amendments to the House bill. One included
language stipulating that none of the budgeted funds may be used to pay for
more than fifty federal employees to attend any conference or meeting outside
the United States. This could make federal attendance at many important meetings
problematic. The second amendment took funding away from two peer-reviewed NIMH
grant applications involving the study of college student mental health because
they were deemed not to be important research topics.

The Senate passed the Genetic Information Nondiscrimination Act of 2003 (S.
1053). However, it has languished in the House this year despite attempts to
move it along. The Subcommittee on Employer and Employee Relations, of the Committee
on Education and the Workforce, held a hearing on July 22, 2004, entitled "Genetic
Non-Discrimination: Examining the Implications for Workers and Employers."
The witnesses included Dr. Kathy Hudson, the director of the Genetics and Public
Policy Center of Johns Hopkins University and former NHGRI staffer. After the
hearing, Chairman Sam Johnson (R-TX) made it clear to the press that his committee
would not pass such legislation this year. We have also seen action from the
Secretary's Advisory Committee on Genetics Health and Society (SACGHS) on this
issue. The SACGHS is also planning a hearing on this topic at their October
meeting, to give those who may have been discriminated against a chance to go
on record with their stories. This issue remains a priority for NHGRI and we
will continue to work on it when the new Congress starts next year.

Report from the Department of Energy

Aristides Patrinos reported on the budget situation at the U.S. Department
of Energy (DOE), which continues to be grim. However, the DOE Joint Genome Institute
sequencing production facility continues to increase its efficiency and is currently
generating 2.4 Gigabases of raw sequence per month. In FY2005, 30 billion base
pairs of sequence production is projected. An analysis of the human chromosome
5 sequence will be published soon in Nature. A paper describing the sequence
of human chromosome 16 is currently under review. The poplar genome sequencing
project has reached eight-fold genome sequence coverage, an assembly has been
generated and annotated, and an annotation jamboree is scheduled. The Xenopus
tropicalis genome is currently at seven-fold sequence coverage. Other sequencing
projects include: Amphioxus, Daphnia pulex, Nematostella and 31 microbial projects.

The DOE's community sequencing project was launched earlier this year. This
project involves the transformation of the sequencing facility at Walnut Creek
to a community service facility. Of sixty proposals received from the community,
twenty-four were funded. Ten of these are microbial projects, ten are basal
organisms and four involve ESTs or targeted sequencing projects. A meeting of
the advisory committee to the Genomes to Life program will take place soon.
In addition, progress is being made regarding the DOE's effort to establish
high-end biocomputing resources.

Council Members as Special Government Employees

Barbara Fuller presented information regarding the role of council members
as special government employees. As special government employees, council members
are governed by the conflict of interest statutes. Under special circumstances,
waivers to the statutes can be granted. Council members are encouraged to provide
detailed information regarding situations requiring a waiver at the time that
council members submit conflict of interest issues to NHGRI. Financial disclosure
updates are required before each council session. It is also important to let
NHGRI know of any relationships with foreign countries and institutions.

Peter Good presented a concept clearance for training institutional bioinformatics
resource specialists - "training the trainers." Strong support for
this initiative came from a meeting last year about HumanBase. That group recognized
that many biological researchers in the community do not know how to use the
many tools available to access genome informatics resources. This concept proposes
to train instructors who can disseminate information at their home institutions.
Career development awards would be made. Awardees would attend training sessions
with NHGRI and receive curricula to take back to their institutions. NHGRI confirmed
that they would appropriately evaluate the program. Institutional library resources
are natural conduits for this program. Reaching out to high schools and learning
from established similar programs are also options. The scale covered by this
concept is probably not large enough to address this overall issue, and NHGRI
should look to partner with other NIH institutes and societies such as ASHG.
Council approved the concept.

Summary Report from the Sequencing Advisory Panel on the NHGRI Large-Scale
Sequencing Program

The sequencing program started by funding numerous pilot projects to sequence
the human genome. Since then a smaller number of centers were ramped up, reaching
a peak of activity at the time of completing the human genome. Funds for the
program have since decreased, while sequence capacity has continued to rise.
Currently the five centers are able to sequence 90 Gigabases of raw sequence,
which is equivalent to 30 single-pass coverages of a mammalian-sized genome.
Further increases in efficiency are still to come. The centers are also involved
in significant bioinformatics, technology development, mapping, outreach and
community coordination efforts. These efforts make up about 20% of the overall
sequencing budget. Production sequence costs have decreased over time. It cost
about $10 in 1990 to produce a finished base compared with approximately six
cents today.

To date, genome sequencing has been completed for a number of organisms. Finishing
also remains a priority for the NHGRI sequencing program. The data for genomes
are clearly being used by the community as evidenced by the hits to the various
web browsers for human, mouse and rat genomes. There are a number of reasons
for continued genome sequencing, including: generating reference sequences for
important experimental organisms and annotating the human genome by comparative
sequence analysis, the best approach for which is currently under debate. A
number of mammals in the sequencing queue were chosen to provide a substantial
amount of evolutionary branch length to enable informative comparative analyses.
Primate species are also in the pipeline to provide comparative information
at closer evolutionary distances. Non-mammalian vertebrates and invertebrates
are also being sequenced for a number of reasons: particular biological interests,
to fill niches of the evolutionary tree or to annotate model systems. Large-scale
sequencing capacity could also include human resequencing.

Council discussed the amount of resources devoted to technology development
at the centers and the resulting effect on sequence capacity and quality. Historically,
if more funds had been spent on technology development, would sequence quality
and production capacity currently be better and/or greater? Not necessarily;
while the centers have not been the places for breakthrough technologies, they
have made substantial improvements to their own pipelines. The funding system
has been built in a way to allow the centers to try new technologies. The amount
of pressure on the centers to reduce costs and increase efficiencies has been
historically optimal. New technologies should be pushed just as hard.

It is very important to get a new technology in place in the next two to three
years and to decrease its required infrastructure. The next generation of sequencing
technology (~ten years) needs to have a further drop in reagent cost, an even
smaller infrastructure and a drop in hardware cost. As technology improves and
capacity increases, other aspects of sequencing, such as informatics, assembly
and annotation may become rate-limiting.

Where possible, partnerships with private industry should be built. It was
noted that the current NIH rules for SBIR grants tend to chase private money
out of technology development, because of the limit to private ownership, which
is currently 50%. In addition, the current sequencing pipeline is dependent
on Applied Biosystems, who is not currently developing new sequencing machines.

When evaluating the sequencing centers, there is a tendency to stress cost
figures and data generation. There are many additional important center activities
including community interaction, accommodation of the needs of different organisms,
project management and mapping. Finishing hasn't improved that much over time,
but this is due to focus being put on the delivery of other levels of sequence
data. Council agreed that the ability to finish is an ability that should not
be lost. It was also noted that there is a portion of the genome, heterochromatin,
that we are still unable to sequence.

The sequencing centers recognize that NHGRI support for sequencing is decreasing.
As other funding agencies are able to support sequencing, the sequencing centers
are increasing and diversifying their portfolio of projects. Even though the
sequencing pipeline is now high throughput and automated, there are aspects
of the sequencing process such as assembly and annotation that remain difficult
research problems. The centers are uniquely qualified to handle these difficulties.
Also, even though there are many research entities interested in technology
development, they will not be sites for data production. Therefore, data generation
needs to be sustained at some level; at least until the next generation of sequencing
technology is established.

NHGRI-supported sequencing comprises over half of the worldwide sequencing
capacity.
NHGRI is the leader in maintaining sequencing capacity, driving technology development
and coordinating sequencing efforts with other institutions and funding agencies.
The International Sequencing Consortium meets annually and supports a website
of sequencing projects in order to help coordinate international sequencing
efforts. NHGRI maintains communication with DOE and the Wellcome Trust, as well
as other entities. It was suggested that NHGRI consider collaborations with
Singapore and India.

It was noted that dialogue regarding sequencing has evolved from 'simple' sequence
generation to addressing scientific questions. The next round of sequencing
recommendations will address the identification of conserved elements, informing
other model organisms, human resequencing, additional primate sequencing and
finishing of some genomes. The new plans will be presented to council in the
February and May council sessions.

HapMap Update

Lisa Brooks provided an update on the HapMap Project, an international effort
to generate a haplotype map for the entire human genome. The genotyping on 270
samples from four populations currently proceeds in two phases. Phase I aims
to produce a SNP every 5 kilobases. The second phase will increase the SNP coverage
and involve a total of ~3 million SNPs, to improve the choice of tag SNPs. There
are currently eight international groups participating in genotyping efforts.
A quality assessment exercise has taken place, with a second currently in process
and a third scheduled.

Most chromosomes are 60-80% complete in terms of SNP coverage in the "Hap-Mappable"
genome for the 5 kb map. In order to define the rules for completing the map,
deeper data are being generated for a small number of regions. Additional SNP
discovery was done in ten of the ENCODE regions and all known SNPs will be genotyped
in these regions. The third phase of the HapMap involves examining the ENCODE
regions in additional populations and comparing the patterns between populations.
Sample collection efforts are currently underway for these populations.

Council discussion included the extension of the numbers of individuals rather
than the number of populations. This will be done in ten of the ENCODE regions,
where an additional 270 samples from the four populations will be genotyped.
It was also noted that a haplotype map does not answer all types of research
questions. Additional work will be needed to identify all SNPs at a lower minor
allele frequency threshold.

Memorandum of Understanding

Cheryl Chick went over the Statement of Understanding that outlines the relationship
between the NHGRI and the Council regarding the review of grant applications
and staff administrative authorities. Council concurred with the statement as
written. Given the size of some NHGRI grants, council expressed some concern
with language giving authority to NHGRI to award administrative supplements
of up to 25% of a grant's budget without Council approval. The statement will
be presented again to February 2005 council for its regular annual approval.
NHGRI will modify the MOU to reflect Council comments regarding the 25% supplement
authority. In the interim, the Council approved the statement as written.

Council-Initiated Discussion

In February 2005, we will have a discussion of the CEGS program, a presentation
about the NIH Roadmap and a presentation of the results of the sequencing center
site visits. Mary Hendrix suggested a presentation regarding epigenetic analysis.
It was noted that a recently awarded CEGS project deals with this issue. The
PI, Andy Feinberg, could be invited to present at the May Council session. Rick
Myers suggested a presentation regarding resequencing technologies.

Announcements and Items of Interest

Dr. Guyer noted one item of interest in the Council folders, a notice regarding
supplements to promote reentry of scientists into biomedical and behavioral
research centers.

Conflict of Interest

Dr. Guyer read the Conflict of Interest policy to Council and asked them to
sign the forms provided.